title: Extracellular hemin crisis triggers acute  chest syndrome in sickle mice.
abstract: The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. We tested the hypothesis that the hemolysis byproduct hemin elicits events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and autoamplification of extracellular hemin in transgenic sickle mice, but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, we confirmed that TLR4 expressed in nonhematopoietic vascular tissues mediated this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. Our results reveal a mechanism that helps to explain the pathogenesis of ACS, and we provide proof of principle for therapeutic strategies to prevent and treat this condition in mice.
authors.forename: Samit
authors.initials: S
authors.lastname: Ghosh
authors.forename: Olufolake Adetoro
authors.initials: OA
authors.lastname: Adisa
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Chappa
authors.forename: Fang
authors.initials: F
authors.lastname: Tan
authors.forename: Kesmic Ann
authors.initials: KA
authors.lastname: Jackson
authors.forename: David Robert
authors.initials: DR
authors.lastname: Archer
authors.forename: Solomon Fiifi
authors.initials: SF
authors.lastname: Ofori-Acquah
mesh_terms: D056586:Acute Chest Syndrome / Q000097:blood / Q000209:etiology* / Q000517:prevention & control; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D006427:Hemin / Q000378:metabolism*; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006461:Hemolysis; D006466:Hemopexin / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000627:therapeutic use; D012805:Sickle Cell Trait / Q000097:blood / Q000150:complications / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D006451:Hemoglobin, Sickle; D011994:Recombinant Proteins; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D006427:Hemin; D006466:Hemopexin